Application of bradykinin in preparation of medicine for reducing food intake and medicine composition

Abstract

The invention provides application of bradykinin to preparation of a medicine for reducing food intake and a medicine composition, and belongs to the technical field of biological medicine. Application of the bradykinin or the pharmaceutically acceptable derivative of the bradykinin comprises application of the bradykinin to preparation of drugs for reducing food intake, and the bradykinin has an amino acid sequence as shown in SEQ ID No.1. Bradykinin can inhibit food intake through a peripheral receptor and reduce body weight instead of playing a role through a central nervous system; the bradykinin can further significantly reduce the food intake of the mouse and reduce the weight of the mouse, it can be proved that bradykinin has the potential of treating obesity, can be applied to preparation of drugs for treating and inhibiting food intake or obesity, is an endogenous substance, is high in safety and relatively small in side effect, acts on the peripheral system, and has a good application prospect. And side effects of central nervous system drugs are avoided.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to an application of bradykinin as a drug for preparing a drug for reducing food intake, and a drug composition. Background Art

[0002] There is a close pathophysiological relationship between obesity and a variety of metabolic diseases, the most prominent of which are cardiovascular diseases such as type 2 diabetes, hypertension, and coronary atherosclerotic heart disease. In addition, obesity may also cause a variety of complications such as sleep apnea syndrome, osteoarthritis, and non-alcoholic fatty liver disease, which seriously affect the patient's quality of life and life expectancy.

[0003] At present, the clinical treatment of obesity mainly adopts a multimodal comprehensive intervention strategy, including lifestyle intervention such as diet control and exercise therapy, drug therapy, and surgery. Among them, lifestyle intervention as a basic treatment method is safe but has limited effects, and it is often difficult to adhere to for a long time; surgical intervention such as gastric bypass surgery, although effective, has high risks and high costs, and is only suitable for patients with severe obesity. In terms of drug treatment, related drugs such as orlistat and liraglutide have certain therapeutic effects, but they generally have side effects such as gastrointestinal adverse reactions and cardiovascular risks, and the long-term treatment effect is limited. Therefore, it is necessary to develop new anti-obesity drugs with better safety, more significant weight loss effects, and multiple benefits of improving metabolic indicators. Summary of the invention

[0004] In view of this, in order to at least partially solve the above-mentioned technical problems, the present invention provides a use of bradykinin as a drug for preparing a drug for reducing food intake and a pharmaceutical composition.

[0005] According to an embodiment of the present invention, there is provided an application of bradykinin or a pharmaceutically acceptable derivative thereof, the application comprising the application of bradykinin for preparing a drug for reducing food intake, wherein the bradykinin has an amino acid sequence shown in SEQ ID No.1.

[0006] According to an embodiment of the present invention, bradykinin inhibits feeding and reduces food intake via peripheral receptors.

[0007] According to an embodiment of the present invention, the application also includes the application of bradykinin as a drug for treating obesity and / or reducing body weight.

[0008] According to an embodiment of the present invention, the application includes salifying bradykinin, and / or chemically modifying the amino acid sequence shown in SEQ ID No.1.

[0009] According to an embodiment of the present invention, the salt of bradykinin includes at least one of a metal salt of bradykinin, a salt of bradykinin and an inorganic acid, and a salt of bradykinin and an organic acid; the chemical modification of the amino acid sequence shown in SEQ ID No.1 includes at least one of acetylation, amination, methylation, phosphorylation, glycosylation, liposylation, ubiquitination, biotin labeling, and fluorescent protein labeling.

[0010] According to an embodiment of the present invention, the metal salt of bradykinin includes at least one of lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, manganese salt, copper salt, zinc salt, and aluminum salt; the inorganic acid includes hydrochloric acid, sulfuric acid, boric acid or carbonic acid; the organic acid includes at least one of acetic acid, citric acid, lactic acid, malonic acid, maleic acid, tartaric acid, fumaric acid, benzoic acid, aspartic acid, glutamic acid, succinic acid, oleic acid, trifluoroacetic acid, and oxalic acid.

[0011] According to an embodiment of one aspect of the present invention, a pharmaceutical composition is provided, which is used to reduce food intake and / or treat obesity; the pharmaceutical composition comprises bradykinin having an amino acid sequence shown in SEQ ID No. 1 or a pharmaceutically acceptable derivative thereof as an active ingredient.

[0012] According to an embodiment of the present invention, the derivative includes a salt of bradykinin and / or a chemical modification of bradykinin.

[0013] According to an embodiment of the present invention, the dosage form of the pharmaceutical composition is any one of an aerosol, a spray, a powder, a pill, a tablet, a film, an ointment, a suppository, a paste, a solution, an injection, a mixture, a lotion or a liniment.

[0014] According to an embodiment of the present invention, the dosage of the pharmaceutical composition is 0.1-100 mg / kg.

[0015] According to the embodiment of the present invention, the present invention proposes that bradykinin can inhibit eating and reduce body weight through peripheral receptors rather than through the central nervous system; further, it can significantly reduce the food intake of mice and reduce the weight of mice, which can prove that bradykinin has the potential to treat obesity and can be used in the preparation of drugs for treating eating inhibition or obesity. Moreover, bradykinin is an endogenous substance with high safety and relatively small side effects. Moreover, bradykinin acts on the peripheral system, avoiding the side effects of central nervous system drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This is a comparison chart showing the effects of intraperitoneal injection of bradykinin and phosphate buffered saline (PBS) on the food intake of mice in Example 1 of the present invention;

[0017] Figure 2This is a comparison chart of the effects of intraperitoneal injection of bradykinin and PBS on the body weight of mice in Example 1 of the present invention;

[0018] Figure 3 This is a comparison chart of the effects of intracerebroventricular injection of bradykinin and PBS on the food intake of mice in Example 2 of the present invention;

[0019] Figure 4 This is a comparison chart of the effects of intracerebroventricular injection of bradykinin and PBS on mouse body weight in Example 2 of the present invention. DETAILED DESCRIPTION

[0020] Below, embodiments of the present invention will be described with reference to the accompanying drawings. However, it should be understood that these descriptions are exemplary only and are not intended to limit the scope of the present invention. In the following detailed description, for ease of explanation, many specific details are set forth to provide a comprehensive understanding of embodiments of the present invention. However, it is apparent that one or more embodiments may also be implemented without these specific details. In addition, in the following description, descriptions of known structures and technologies are omitted to avoid unnecessary confusion of concepts of the present invention.

[0021] The terms used herein are only for describing specific embodiments and are not intended to limit the present invention. The term "comprising" used herein indicates the existence of features, steps, operations, but does not exclude the existence or addition of one or more other features.

[0022] In the present invention, the term "pharmaceutically acceptable" refers to compounds, substances, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0023] The term "treatment" means that after a subject has a disease, the subject is exposed to (e.g., administered) a drug, composition, etc. according to the present invention, thereby alleviating the symptoms of the disease compared to when the subject has not been exposed to the drug, composition, etc., and does not necessarily mean that the symptoms of the disease are completely suppressed. Suffering from a disease means that the body has symptoms of the disease.

[0024] In the process of realizing the concept of the present invention, it was found that bradykinin is a bioactive peptide composed of 9 amino acids, which plays a key role in various physiological and pathological processes mainly by activating two G protein-coupled receptors (GPCRs), B1 and B2. Previous studies have shown that it has important functions in inflammatory response, vasodilation, blood pressure regulation, pain perception, etc., but its potential in the treatment of obesity has not yet been explored.

[0025] Specifically, according to an embodiment of one aspect of the present invention, there is provided an application of bradykinin or a pharmaceutically acceptable derivative thereof, the application comprising the application of bradykinin for preparing a drug for reducing food intake, wherein the bradykinin has an amino acid sequence shown in SEQ ID No. 1.

[0026] According to the embodiment of the present invention, the present invention proposes that bradykinin can inhibit eating and reduce body weight through peripheral receptors rather than through the central nervous system; further, it can significantly reduce the food intake of mice and reduce the weight of mice, which can prove that bradykinin has the potential to treat obesity and can be used in the preparation of drugs for treating eating inhibition or obesity. Moreover, bradykinin is an endogenous substance with high safety and relatively small side effects. Moreover, bradykinin acts on the peripheral system, avoiding the side effects of central nervous system drugs.

[0027] According to an embodiment of the present invention, the amino acid sequence shown in SEQ ID No. 1 is: RPPGFSPFR, or Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg, which is a linear nonapeptide.

[0028] According to an embodiment of the present invention, bradykinin inhibits feeding and reduces food intake via peripheral receptors.

[0029] According to the embodiments of the present invention, bradykinin regulates appetite-related signaling pathways by binding to B1 and B2 receptors in peripheral tissues such as the gastrointestinal tract or blood vessels, affecting the secretion of gastrointestinal hormones such as cholecystokinin and glucagon-like peptide-1 (GLP-1), thereby reducing hunger or enhancing satiety, and ultimately achieving the effect of reducing food intake. This mechanism avoids the possible side effects of direct action on the central nervous system and has higher safety and controllability.

[0030] According to an embodiment of the present invention, the application also includes the application of bradykinin as a drug for treating obesity and / or reducing body weight.

[0031] According to an embodiment of the present invention, bradykinin can effectively reduce energy intake by reducing food intake and suppressing appetite, thereby helping to control body weight and treat obesity.

[0032] According to an embodiment of the present invention, the application includes salifying bradykinin, and / or chemically modifying the amino acid sequence shown in SEQ ID No.1.

[0033] According to an embodiment of the present invention, the stability, bioavailability or efficacy of bradykinin is improved by salification or chemical modification of the amino acid sequence of bradykinin. Saltization and chemical modification can improve the pharmacokinetic properties of bradykinin, such as extending the half-life, enhancing targeting or reducing degradation, thereby improving its effect and convenience in practical applications.

[0034] According to an embodiment of the present invention, the salt of bradykinin includes at least one of a metal salt of bradykinin, a salt of bradykinin and an inorganic acid, and a salt of bradykinin and an organic acid; the chemical modification of the amino acid sequence shown in SEQ ID No.1 includes at least one of acetylation, amination, methylation, phosphorylation, glycosylation, liposylation, ubiquitination, biotin labeling, and fluorescent protein labeling.

[0035] According to an embodiment of the present invention, the salt refers to a salt recognized for use in animals, and more specifically in humans, including metal salts of the amino acid sequence shown in SEQ ID No.1, the metal including but not limited to lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc or aluminum, etc.; including salts formed by the amino acid sequence shown in SEQ ID No.1 and organic bases, including but not limited to ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine or piperazine, etc.; including salts formed by the amino acid sequence shown in SEQ ID No.1 and inorganic acids or organic acids, including but not limited to acetic acid, citric acid, lactic acid, malonic acid, maleic acid, tartaric acid, fumaric acid, benzoic acid, aspartic acid, glutamic acid, succinic acid, oleic acid, trifluoroacetic acid, oxalic acid, pamoate or gluconic acid, etc.; inorganic acids including but not limited to hydrochloric acid, sulfuric acid, boric acid or carbonic acid.

[0036] According to another embodiment of the present invention, a pharmaceutical composition is provided, which is used to reduce food intake and / or treat obesity; the pharmaceutical composition comprises bradykinin having an amino acid sequence shown in SEQ ID No. 1 or a pharmaceutically acceptable derivative thereof as an active ingredient.

[0037] According to an embodiment of the present invention, the pharmaceutical composition further comprises bradykinin and a pharmaceutically acceptable derivative thereof.

[0038] According to an embodiment of the present invention, when the pharmaceutically active ingredient is a pharmaceutically acceptable salt, such as a pharmaceutically acceptable acid addition salt or base addition salt, it can react with a pH adjuster in the solution to prepare in situ the corresponding free active ingredient, such as a free alkaline active ingredient or a free acidic active ingredient.

[0039] According to an embodiment of the present invention, the dosage form of the pharmaceutical composition is any one of an aerosol, a spray, a powder, a pill, a tablet, a film, an ointment, a suppository, a paste, a solution, an injection, a mixture, a lotion or a liniment.

[0040] According to the embodiments of the present invention, the dosage forms of various drugs meet different treatment needs, improve patient compliance, optimize drug efficacy and safety, can meet different clinical needs and patient preferences, and adapt to different routes of administration.

[0041] Specifically, auxiliary ingredients may also be included, including at least one of preservatives, solubilizers, stabilizers, diluents, and lubricants. The auxiliary ingredients can improve the physical and chemical properties of the drug, improve the efficacy and safety of the drug, and increase the acceptability of the preparation, meet different clinical needs and patient preferences, and at the same time help the stable release and effective delivery of the drug, and also improve the safety of the preparation. By rationally selecting and using these excipients, the dosage form of the drug can be optimized and the therapeutic effect can be improved.

[0042] According to an embodiment of the present invention, the dosage of the pharmaceutical composition is 0.1-100 mg / kg.

[0043] According to an embodiment of the present invention, the dosage can be 0.1 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0044] According to the embodiment of the present invention, the administration method is preferably by intraperitoneal injection, but is not limited to intraperitoneal injection only, and can be administered by other methods such as oral administration by adjusting the appropriate dosage form.

[0045] The scheme of the present invention will be further explained below with reference to specific examples. Unless otherwise stated in the following examples, conventional commercial reagents are used.

[0046] In the result graphs of the following examples, * indicates a P value < 0.05, ** indicates a P value < 0.01, and *** indicates a P value < 0.001. A P value < 0.05 is considered to have a statistically significant difference. The data values ​​are represented by the mean value (n is the total number of experimental groups) ± standard error in the statistical result graphs.

[0047] Example 1 Effects of intraperitoneal injection of bradykinin on diet and body weight of mice

[0048] Experimental animals: 8-week-old male C57BL / 6J mice with normal development were selected as experimental subjects and divided into experimental group and control group. Before the formal experiment, the mice were housed individually for 3 days to adapt.

[0049] Drug preparation: Dissolve bradykinin in PBS buffer to prepare a solution of appropriate concentration, and prepare it before use.

[0050] Intraperitoneal injection experiment: After fasting for 12 hours overnight, the two groups of mice were fixed, and an appropriate amount of bradykinin solution was drawn with a 1 ml syringe and slowly injected into the peritoneal cavity at the lower 1 / 3 of the mouse abdomen, avoiding the internal organs. The bradykinin dose for intraperitoneal injection was 10 mg / kg, and the control group was injected with an equal amount of PBS buffer, and the operation steps were the same as those of the experimental group.

[0051] The food intake of mice was monitored for 5 hours, that is, the food intake at 0, 0.5, 1, 1.5, 2, and 5 h was monitored. Figure 1 Bradykinin or PBS was injected at the same time point every day for one week, and the weight of the mice was recorded at the same time point before the injection of the drug every day. The results are shown in Figure 2 shown.

[0052] Figure 1 This is a comparison chart of the effects of intraperitoneal injection of bradykinin and PBS on the food intake of mice in Example 1 of the present invention; Figure 2 This is a comparison chart of the effects of intraperitoneal injection of bradykinin and PBS on mouse body weight in Example 1 of the present invention.

[0053] according to Figure 1 and Figure 2 It can be seen that after intraperitoneal injection of bradykinin, the food intake of mice was significantly reduced, and after continuous injection for one week, the weight of mice showed a downward trend.

[0054] Example 2 Effects of intracerebroventricular injection of bradykinin on diet and body weight in mice

[0055] Experimental animals: 8-week-old male C57BL / 6J mice with normal development were selected as experimental subjects and divided into experimental group and control group. Before the formal experiment, the mice were housed individually for 3 days to adapt.

[0056] Drug preparation: Dissolve bradykinin in PBS buffer to prepare a solution of appropriate concentration, and prepare it before use.

[0057] Intracerebral ventricle injection experiment: The mice in both the experimental and control groups were implanted with cannulas in the lateral ventricles using a stereotaxic instrument, and the experimental operation was performed after the mice recovered for one week. After the two groups of mice were fasted overnight for 12 hours, bradykinin was injected into the lateral ventricle through the cannula with the help of a microinjection pump. The dose of bradykinin injected into the lateral ventricle was 10 nM / 2μl. The control group was injected with an equal amount of PBS buffer, and the operation steps were the same as those of the experimental group.

[0058] The food intake of mice was monitored for 5 hours after intracerebroventricular injection of bradykinin, i.e., food intake was monitored at 0, 0.5, 1, 1.5, 2, and 5 h. Figure 3 Bradykinin or PBS was injected at the same time point every day for one week, and the weight of the mice was recorded at the same time point before the injection of the drug every day. The results are shown in Figure 4 shown.

[0059] Figure 3 This is a comparison chart of the effects of intracerebroventricular injection of bradykinin and PBS on the food intake of mice in Example 2 of the present invention; Figure 4 This is a comparison chart of the effects of intracerebroventricular injection of bradykinin and PBS on mouse body weight in Example 2 of the present invention.

[0060] according to Figure 3 and Figure 4 It can be seen that after intracerebroventricular injection of bradykinin, the food intake of mice did not change significantly, and continuous injection for one week had no obvious effect on the weight of mice.

[0061] In summary, bradykinin inhibits eating and reduces weight through peripheral receptors rather than through the central nervous system.

[0062] The specific embodiments described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A use of bradykinin or a pharmaceutically acceptable derivative thereof, characterized in that: The application includes the application of the bradykinin for preparing a drug for reducing food intake, The bradykinin has an amino acid sequence shown in SEQ ID No.

1.

2. The use according to claim 1, characterized in that: The bradykinin inhibits food intake and reduces food intake via peripheral receptors.

3. The use according to claim 1, characterized in that: The application also includes the application of the bradykinin as a drug for treating obesity and / or reducing body weight.

4. The use according to claim 1, characterized in that: The application includes salifying the bradykinin, and / or chemically modifying the amino acid sequence shown in SEQ ID No.

1.

5. The use according to claim 4, characterized in that: The salt of bradykinin includes at least one of a metal salt of bradykinin, a salt of bradykinin and an inorganic acid, and a salt of bradykinin and an organic acid; The chemical modification includes at least one of acetylation, amination, methylation, phosphorylation, glycosylation, lipidation, ubiquitination, biotin labeling, and fluorescent protein labeling.

6. The use according to claim 5, characterized in that: The metal salt of bradykinin includes at least one of lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, manganese salt, copper salt, zinc salt and aluminum salt; The inorganic acid includes hydrochloric acid, sulfuric acid, boric acid or carbonic acid; the organic acid includes at least one of acetic acid, citric acid, lactic acid, malonic acid, maleic acid, tartaric acid, fumaric acid, benzoic acid, aspartic acid, glutamic acid, succinic acid, oleic acid, trifluoroacetic acid and oxalic acid.

7. A pharmaceutical composition, characterized in that The pharmaceutical composition is used for reducing food intake and / or treating obesity; The pharmaceutical composition comprises bradykinin having an amino acid sequence shown in SEQ ID No. 1 or a pharmaceutically acceptable derivative thereof as an active ingredient.

8. The pharmaceutical composition according to claim 7, characterized in that The derivatives include salts of the bradykinin and / or chemically modified products of the bradykinin.

9. The pharmaceutical composition according to claim 7, characterized in that The dosage form of the pharmaceutical composition is any one of aerosol, spray, powder, pill, tablet, film, ointment, suppository, paste, solution, injection, mixture, lotion or liniment.

10. The pharmaceutical composition according to claim 7, characterized in that The dosage of the pharmaceutical composition is 0.1-100 mg / kg.

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